ENAC

Question

Hello,

My question is complex. At the age of 22 months, my daughter has been diagnosed with CF because of gut and respiratory problems. The neonatal screening test at birth was negative (premature 33 gestaional weeks; 1.8kg) but, at diagnostic, the sweat test was highly positive (>200). Then, she had several problems, respiratory infections, maltophilia in the airways, staphylococcus and pseudomonas, that were treated by ciprofloxacin and Tobramycin. A second sweat test several months later was performed because no CFTR mutations could be found. This test was, again, very positive, with a decreased fecal elastase up to 50! Since then, several corticosteroid therapies had been necessary because of a severe airway hyperresponsiveness. As such, she had an adrenal insufficiency for more than a year, so she required a substitutive therapy with hydrocortisone. In October, we went to perform other tests to assess why, despite the absence of CFTR mutations, she had a marked phenotype. A new sweat test was then negative with a fecal elastase that came back to normal (I did not know that such decreased level could be reversible)!!! A NPD (nasal potential difference) measurement and a rectal biopsy confirmed the absence of abnormality in CFTR BUT, on the contrary, an important reaction to amiloride that led to highly suggest a problem in the ENaC channel. Since then, we don’t know anything more. What do you think of this atypical case? Are we still talking about CF? Is the evolution known? As parents, we are lost by all of this. I know that the medical doctors are also perplexed, but we need answers and need to know if other cases have been reported. Thanks for the answers you could provide me.

Answer

Hello

Your daughter’s story with, in particular, positive and negative sweat chloride tests, without CFTR mutations, and this recent result of the nasal potential difference (NPD), suggests indeed a dysfunction not of CFTR (channel not functional or absent in the case of CF) but of ENaC (epithelial sodium channel amiloride sensible). This disease, if confirmed, is called pseudohypoaldosteronism.

Some symptoms are indeed similar when one of these 2 channels isn’t functional. Normally, ENaC reabsorbs sodium and water in the cells, regulating the hydration of the cell surface, and, so, the hydration of many organs such as lungs, skin, pancreas, intestine. CFTR interacts with ENaC inhibiting its activity.

So, in CF, when CFTR isn’t functional, ENaC isn’t inhibited and the cells absorb too much water and salt, with consequences in those organs. For example, in the lungs, the mucus is dehydrated, favoring airways obstruction, that lead to chronic inflammation and recurrent infections (with, for example, bacteria such as the ones you listed for your daughter).

In the pseudohypoaldosteronism, it’s not CFTR but ENaC that is not functional. Thus, the airways’ mucus is not dehydrated but the volume of airway surface liquid increased, leading also to frequent respiratory tract manifestations, mimicking cystic fibrosis.

It’s known that some patients with pseudohypoaldosteronism have positive sweat chloride tests, that could increase the difficulties in diagnosis. There is indeed, in the pseudohypoaldosteronism, salt wasting in several organs, among which salt wasting in the sweat glands.

It’s a genetic disease, transmitted in an autosomal recessive manner. Some ENaC mutations are known and could be searched for. There are other biological signs that could be search for, such as increased blood levels of potassium, renin and aldosterone.

I’m not an expert of this disease but it seems that, although the patients require life-long salt supplementations, their symptoms could improve with time, with a decrease in salt-wasting episodes and respiratory tract infections.

My advice would be to discuss with the medical doctors of your CF center, to see which complementary investigations would be appropriate for your daughter. You may also look at the Orphanet website for more info on this disease in particular.

Best regards

Harriet Corvol

10.02.2014